The role of Mycoplasma genitalium in human disease has been difficult to define. The organism is frequently mixed with M. pneumoniae and these two organisms share considerable immunologic reactivity. Thus, conventional complement-fixation tests or new immunosorbent assays for M. pneumonia infections can not differentiate serologic responses to each organism. We now have also identified mixed M. genitalium/M. pneumoniae strains in the synovial fluid of a patient with polyarthritis following primary pneumonia infection, suggesting that M. genitalium can become disseminated from either urogenital or oropharynx sites. We have currently defined an indirect immuno-fluorescence assay that will accurately distinguish colonies of each organism on agar plates when mixed strains are grown in culture. This test is being applied to specimens being compared in culture versus direct testing with a variety of molecular probes. Collaborative studies have also established that animal mycoplasmas (M. arginini) can induce severe and fatal infections in immunocompromised patients. The inability of antibiotic drugs to control such infections is related to the mycoplasmastatic activity of known antibiotics and the contribution of an intact humoral and cell mediated defense in the host. Taxonomic characterization of a new mycoplasma from the urine of both HIV- positive and AIDS patients has been carried out in collaborative studies. The high cytopathogenicity for a variety of eukaryotic cells appears related to the unique attachment structure on the organism and the ability of the organism to induce intra-cellular infections. The organism has been designated Mycoplasma penetrans.